Mutations in the methyl CpG binding protein 2 (MeCP2) are the primary cause of the neurodevelopmental disorder, Rett syndrome (RTT). The current model predicts that MeCP2 functions in vivo to mediate transcriptional silencing by recruiting histone deacetylases to methylated cytosine residues throughout the genome. While the recent discovery of MeCP2 as the causative gene behind RTT provided a genetic marker to diagnosis the disorder, there is no link between the loss of function of MeCP2 and the etiology of RTT. The proposed studies will test the hypothesis that loss of function of MeCP2 will lead to the misexpression of genes that will ultimately cause neuronal dysfunction. Dysregulated genes will be identified from an immortalized neuronal cell line where MeCP2 activity has been disrupted. The loss of MeCP2 function in vitro and in vivo will be examined for involvement in neurite outgrowth and dendritic arborization. While commonly occurring mutations in MeCP2 will be studied to look at whether they display altered activity in the nucleus. The goal of the proposed study is to bridge the gap between our current understanding of the role of MeCP2 and of the underlying pathogenesis of RTT.